This application is a competitive renewal of a project which has the overall goal of identifying susceptibility genes for rheumatoid arthritis which lie outside of the major histocompatibility complex (MH( We have completed a genome wide screen for allele sharing on an initial population of 300 affected sibling pairs with RA. We have identified five markers with evidence of linkage at the p<O.OO5 level, and an additional 8 markers with linkage at p<O.Ol level of significance. Thus, we are now at a point where candidate regions need to be evaluated further. Specific Aim 1: Confirmation of linkage to rheumatoid arthritis and narrowing of the genetic interval in genetic regions showing preliminary evidence of linkage. We are currently pursuing a replication of our initial linkage results in a second set of 300 sibling pairs. Where evidence of linkage continues to persist, dense mapping for linkage around regions of interest will be performed on a data set of 1,000 sibling pairs. Specific Aim 2: Fine mapping of candidate regions using methods dependent on linkage disequilibrium. Selected regions will be supported by the replication and fi linkage mapping in specific aim 1. Up to three of these regions will be further narrowed using two approaches based on linkage disequilibrium. First, one affected member from each sib pair family will be used in case control studies. Second, an independent population of 1,000 RA patients and both parents will be analyzed by transmission disequilibrium testing. These studies will incorporate haplotypic analyses. Specific Aim 3. Identification and analysis of candidate genes in regions showing linkage and association with RA. We assume that there will be full availability of the human genome sequence by the time we seriously address the specific aim. The end game of gene identification will involve repeated association studies with specific polymorphisms of interest in candidate genes, in conjunction with detailed haplotypic analysis.